Distinct CDR3 conformations in TCRs determine the level of cross-reactivity for diverse antigens, but not the docking orientation.
T cells are known to cross-react with diverse peptide MHC Ags through their alphabeta TCR. To explore the basis of such cross-reactivity, we examined the 2C TCR that recognizes two structurally distinct ligands, SIY-K(b) and alloantigen QL9-L(d). In this study we characterized the cross-reactivity of several high-affinity 2C TCR variants that contained mutations only in the CDR3alpha loop. Two of the TCR lost their ability to cross-react with the reciprocal ligand (SIY-K(b)), whereas another TCR (m67) maintained reactivity with both ligands. Crystal structures of four of the TCRs in complex with QL9-L(d) showed that CDR1, CDR2, and CDR3beta conformations and docking orientations were remarkably similar. Although the CDR3alpha loop of TCR m67 conferred a 2000-fold higher affinity for SIY-K(b), the TCR maintained the same docking angle on QL9-L(d) as the 2C TCR. Thus, CDR3alpha dictated the affinity and level of cross-reactivity, yet it did so without affecting the conserved docking orientation.
Jones
Lindsay L
LL
Department of Biochemistry, University of Illinois, Urbana, IL 61801, USA.
Colf
Leremy A
LA
Stone
Jennifer D
JD
Garcia
K Christopher
KC
Kranz
David M
DM
D000595:Amino Acid Sequence; D000818:Animals; D022801:Complementarity Determining Regions / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017124:Conserved Sequence; D003429:Cross Reactions / Q000235:genetics / Q000276:immunology; D006183:H-2 Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D064532:Histocompatibility Antigen H-2D; D007655:Ketoglutarate Dehydrogenase Complex / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D022801:Complementarity Determining Regions; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D064532:Histocompatibility Antigen H-2D; D009842:Oligopeptides; C440022:QL9 peptide; D016693:Receptors, Antigen, T-Cell, alpha-beta; C088354:p2Ca peptide; D007655:Ketoglutarate Dehydrogenase Complex